The etiology of congenital biliary malformations is unknown. Clinical and experimental observations suggest that the combined effects of estrogens and of a toxic bile salt (lithocholic acid) may interfere with morphogenesis of the biliary system early in gestation, and may produce a variety of intrahepatic lesions in mid-term and late-stage fetuses. Estrogens interfere with canalicular secretory processes, and are implicated in cholestasis of pregnancy. Lithocholic acid has been shown to cause lesions of the extra-hepatic and intrahepatic bile ducts, periportal fibrosis, and inflammation in fetal monkeys and rabbits. Similar changes are characteristically present in congenital atretic malformations of the extrahepatic bile ducts. The teratogenicity of lithocholic acid may be enhanced by the cholestatic action of estrogen, and by interference with detoxification processes involving sulfation. Estrogens and lithocholic acid are both converted to inactive polar sulfate derivatives by sulfotransferases. Estrogen may interfere with this detoxification mechanism, since fetal capacity for sulfation of lithocholate is lower than for estrogen. Moreover, taurolithocholate is the preferred substrate for sulfation, and estrogen has been shown to inhibit conjugation of bile acid with taurine. Taurine prevents formation of lithocholate-induced gallstones in adult rats. We intend to determine the effects of lithocholate and estrogen, and of protein and taurine deficiency on the development of the fetal biliary system, and to study the potential protective action of taurine in organogenesis. The methodology and analytical procedures involved in these studies are in current use by investigators. The objectives of the proposed research are to reproduce the lesions found in congenital biliary malformations, to explore the metabolic and enzymatic mechanisms involved in pathogenesis, and to develop prophylactic approaches to these largely intractable abnormalities.